Recent evidence supports the notion that the spinal cord is the site where anesthetics suppress movement resulting from noxious stimuli. While gains have been made in our understanding of specific neurotransmitter receptors that are modulated by anesthetics, we lack understanding of these anesthetic actions at an ntegrative level, e.g., at which spinal cord locations and types of neurons do anesthetic effects interact to oroduce immobility? To shed light on anesthetic effects on sensorimotor processing, the present proposal will use neurophysiological methods to assess the effects of isoflurane (ISO), halothane (HAL) and propofol (PROP) at several spinal sites (dorsal horn; intermediate and ventral horn) and on anatomically or functionally different neuronal types (wide-dynamic range, nociceptive specific neurons, sensory neurons with ascending projections, pre-motor interneurons). In Aim 1we will test the hypothesis that anesthetics differ in their effects on neurons at different depths in the spinal cord. We hypothesize that ISO will have predominant effects at ventral spinal cord sites, whereas HAL and PROP will have effects on both dorsal and ventral spinal cord sites. In Aim 2 we will test the hypothesis that neurons with ascending projections (such as spinothalamic neurons) are more sensitive to anesthetics as compared to local segmental neurons. Furthermore, in Aim 2, we will test the hypothesis that wide-dynamic range neurons are more resistant to anesthesia compared to nociceptive specific neurons. In Aim 3, we will test the hypothesis that GABA-A antagonism (picrotoxin), glycine antagonism (strychnine) and glutamate agonism (NMDA) will reverse anesthetic depression of spinal cord neuronal function in an anesthetic-specific way, with GABA antagonism being more specific for PROP and glutamate and glycine antagonism being more specific for ISO and HAL. The results will lead to a better understanding of how anesthetics modulate neuronal function at an integrative systems level. Understanding how and where anesthetics act will eventually lead to the development of better and safer anesthetics, thereby decreasing peri-operative morbidity and mortality and improving public health.